There are three main objectives of this research program. First we plan to extend our current studies on the regulation of renal mitochondrial glutamine transport and deamidation by cellular metabolites. Specifically, we plan to test our hypothesis that the concentration of alpha-ketoglutarate in renal cells plays a role in modulating glutamine transport and deamidation. We plan to test the hypothesis in a variety of physiological conditions, and in different species, in which rates of renal ammonia production vary widely. The second phase of the study is concerned with the effects of diabetic ketoacidosis on renal ammonia production. We plan to determine: 1) whether diabetic ketoacidosis produces an increase in total renal ammonia production, and 2) whether renal ammonia production in the diabetic animal responds differently to elevated concentrations of ketone bodies than does ammonia production in the non-diabetic animal. Following investigation of 1) and 2) we plan to determine the cellular mechanism(s) by which ketone bodies inhibit renal ammoniagenesis in normal animals. The third phase of this program is concerned with the regulation of glutamine synthesis in mammalian skeletal muscle. First, we will determine whether or not muscle glutamine synthesis increases during metabolic acidosis. If it does, then we will proceed to investigate the cellular mechanism(s) by which glutamine synthesis is increased during acidosis.